Osmotic devices have demonstrated utility in delivering useful active agents such as medicines, nutrients, food products, pesticides, herbicides, germicides, algaecides, chemical reagents, and others known to those of ordinary skill to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pastilles, pills or capsules and others that use osmotic pressure to control the release of the active agent contained in the core of the osmotic device. Some osmotic devices may also include layers comprising one or more materials that are subject to erosion or that slowly dissolve in the environment of use thereby gradually dispensing the active agent.
Osmotic salts that exhibit an osmotic pressure gradient against an external fluid across the semipermeable wall of the osmotic devices have been used in the core of the osmotic devices for long time. U.S. Pat. Nos. 3,977,404, 4,008,719, 4,014,334, 4,034,758, and 4,077,407 to Theeuwes et al., 4,036,227 and 4,093,708 to Zaffaroni et al., describe that the osmotic salts are used mixed with an agent that has limited solubility in the external fluid with the osmotic salt forming a saturated solution containing agent that is osmotically delivered from the device. The osmotic salts are used by homogenously or heterogeneously mixing the osmotic salt or a mixture of them with an active agent, either before they are charged into the reservoir, or by self-mixing after they are charged into the reservoir. In operation, the osmotic salt attract fluid into the device producing a solution of the osmotic salt which is delivered from the device concomitantly transporting undissolved and dissolved agent to the exterior of the device. U.S. Pat. Nos. 6,248,359 and 6,599,532 to Faour, and 6,569,456, 6,572,890, 6,599,284, 6,599,532, 6,605,302, and 6,613,357 to Faour et al., and 6,521,255 to Vergez et al., teaches the osmotic salts will aid in either the suspension or dissolution of the active ingredient in the core. The osmotic salts can be incorporated to the core of the osmotic device to control the release of the active ingredient therefrom. The above referenced disclosures do not disclose that the release rate of the active ingredient is reduced and the release profile of the active ingredient is modified from one order to another or from one shape to another by increasing the amount of the osmotic salt in the core.
The controlled release of active agents from an osmotic device can occur according to many different release profiles: first order, pseudo-first order, zero order, pseudo-zero order, sigmoidal, delayed, constant rate of release, pulsatile and some combinations thereof. Typically, a drug must have a solubility within the range of 50-300 mg/ml in order to be delivered effectively by an osmotic device.
It is generally well known that highly soluble drug salts can be difficult to formulate into osmotic devices. The more soluble they are, generally the more difficult they are to formulate into osmotic devices. This is because the drug salts tend to dissolve too quickly thereby leading to premature release of the drug, load dumping of the drug or rapid rather than controlled release of the drug. According to McClelland et al. (Pharm. Res. (1991), 8(1), 88-92), drugs with a water solubility of ≦50 mg/ml should be released by an osmotic device in a controlled manner such that ≧95% of the drug load is released according to zero-order kinetics. Drugs with a high water solubility (e.g., ≧300 mg/ml) should be released by an osmotic device in a controlled manner such that only a very small percentage of the drug load is released according to zero-order kinetics. McClelland et al. therefore propose modulation of the drug solubility in an attempt to change the release profile of a drug from first order to zero order. McClelland et al. specifically state that the NaCl must be present in controlled release form as NaCl crystals coated with cellulose acetate butyrate to form mini osmotic pumps. They state, “This pump-in-a-pump design was necessary to prevent the rapid depletion, and large attendant concentration variation, of the solubility modulating agent (sodium chloride) within the diltiazem hydrochloride core tablet environment.” Accordingly, McClelland et al. teach that the desired effect provided by sodium chloride cannot be achieved with uncoated sodium chloride crystals. Apparently according to McClelland et al., uncoated sodium dissolves too quickly to decrease the rate of release of diltiazem.
Due to the complexity of interactions occurring within the core of an osmotic device, no generally applicable approach has been developed to control and reduce the rate of dissolution of very water soluble drugs. In fact, some osmotic device excipients accelerate rather than decelerate the rate of drug release.
The use of sodium chloride as an osmagent in an osmotic device is widely known. The art generally teaches that increasing the amount of osmagent results in an increase of osmotic pressure and thereby an increase in the rate of release of drug from the core of the osmotic device. The prior art discloses osmotic devices having a bi-layered or multi-layered core, wherein at least one of the layers is a “push” or “displacement” layer comprising sodium chloride in combination with an osmopolymer or a water swellable polymer. A push layer is generally inert and does not contain drug. The NaCl serves to draw water within the polymer matrix thereby wetting and swelling the polymer.
An osmotic device having a unitary core comprising a pharmaceutically acceptable salt of a drug in combination with sodium chloride and other excipients is known. In particular, the art discloses osmotic devices having a unitary core comprising drugs such as pseudoephedrine hydrochloride (Johnson et al. in U.S. Pat. No. 6,537,573; Faour et al. in U.S. Pat. No. 6,004,582; Hamel et al. in U.S. Pat. No. 4,801,461; Chen et al. in U.S. Pat. No. 5,458,887, U.S. Pat. No. 5,654,005, and U.S. Pat. No. 5,558,879), venlafaxine hydrochloride (Faour et al. in U.S. Pat. No. 6,352,721), reboxetine methane sulfonate (Seroff et al. in U.S. Pat. No. 6,387,403), carbamazepine (Puthli et al. in U.S. Pat. No. 6,534,090), rofecoxib (Faour et al. in U.S. Pat. No. 6,491,949), cisapride monohydrate (Faour et al. in U.S. Pat. No. 6,004,582), nifedipine (Kettelhoit et al. in U.S. Pat. No. 6,294,201); or other drugs (Chen et al. in U.S. Pat. No. 5,736,159 and U.S. Pat. No. 5,837,379) in combination with sodium chloride and other excipients. The art also discloses osmotic devices having bi-layered or multi-layered cores, wherein one of the layers includes a drug and sodium chloride among other excipients (Wong et al. in U.S. Pat. No. 5,785,994; Kuczynski et al. in U.S. Pat. No. 5,866,164). Osmotic devices having a bi-layered core comprising an active ingredient and sodium chloride in the drug-containing layer are disclosed in U.S. Pat. No. 6,352,721 to Faour, which teaches about three osmotic devices containing a core layer comprising venlafaxine hydrochloride and sodium chloride, cisapride and sodium chloride, and nifedipine and sodium chloride, respectively, U.S. Pat. Nos. 5,674,895, 5,840,754, 5,912,268, 6,124,355, 6,262,115 and U.S. Patent Application No. 20010005728, to Guittard et al., and U.S. Patent Application No. 20010009995 to Gupta et al., which disclose a core layer comprising oxybutynin and sodium chloride, and U.S. Pat. No. 6,387,403 to Seroff et al., which discloses a core layer comprising reboxetine methane sulfonate and sodium chloride. International documents WO03/039519 and WO03/039436 to Vergez et al., disclose osmotic devices comprising bi-layered cores comprising a drug in each layer of the core; drug-layer compositions comprising sodium chloride are exemplified. Osmotic devices having a multi-layered core are disclosed in U.S. Pat. No. 5,785,994 to Wong et al., wherein one of the layers includes a drug, such as diltiazem HCl, and potassium chloride among other excipients. In all above-referenced patents, the osmotic salt is disclosed as an osmagent that increases the osmotic pressure of the core by attracting fluid into the device, and thereby producing a solution or suspension of the active ingredient that is then delivered from the device at increased rate. None of above-referenced patents disclose that the release rate of the active ingredient is reduced and that the release profile of the active ingredient is modified by increasing the amount of the osmotic salt in the core. The weight percentages of sodium chloride and the drug as disclosed in the prior art are highly variable.
However, the art is not consistent regarding use of NaCl in osmotic devices: Ramakrishna et al. (Pharmazie (2001), 56(12), 958-962); and Lin et al. (J. Pharm. Sci. (2002), 91(9), 2040-2046).
Accordingly, the art in this area is unpredictable, meaning that one cannot predict with certainty, or a priori, whether increasing the amount of sodium chloride in an osmotic pump containing a drug salt will decrease or increase the rate of release of the drug salt. This is particularly true for specific drug salt and osmotic salt combinations.
Amantadine is available commercially in the United States in immediate release tablet form and syrup form under the trademark SYMMETREL™ from Endo Pharmaceutical Co. The administration of amantadine for the treatment of Parkinson's disease, Alzheimer's disease and some types of dementia is well known. As noted in the Physician's Desk Reference 56th Ed. 2002, depression, among other mood disorders, is a known adverse reaction to amantadine therapy. Moreover, amantadine is subject to undesirable interactions with a number of other drugs.
U.S. Pat. Nos. 6,217,905, 5,221,536 and 5,190,763 to Ayer et al. and 5,192,550 and 5,057,321 to Edgren et al. of Alza Corporation disclose bi-layered osmotic device formulations containing an anti-Parkinson's drug such as amantadine. In this embodiment, the core is bi-layered and comprises a drug composition and a push-composition. An osmotic salt such as sodium chloride, potassium chloride, or magnesium chloride can be included in the push-composition.
U.S. Pat. No. 5,358,721 to Guittard et al. of Alza Corporation discloses bi-layered osmotic device formulations containing an anti-viral drug such as amantadine. In this embodiment, the core is bi-layered and comprises a drug composition and a push-composition. An osmotic salt such as sodium chloride, potassium chloride, or magnesium chloride can be included in the push-composition.
U.S. Pat. No. 6,284,276 to Rudnic et al. discloses an osmotic pharmaceutical delivery system comprised of a semipermeable wall that maintains its integrity during pharmaceutical delivery and that has a passage through it, and a composition within the semipermeable wall, wherein the composition is comprised of a pharmaceutical agent of limited solubility, a non-swelling agent that enhances the solubility of the pharmaceutical agent, and a non-swelling osmotic agent. The '276 patent mentions amantadine as a drug that is suitable for use in the osmotic device.
It is known in the field of osmotic devices that changing the release profile of a drug can have an effect upon the clinical benefit observed in a patient to which the osmotic device is administered. Depending upon the drug being administered, the disease or disorder being treated, the observed clinical response in a subject and other considerations, a particular controlled release profile will be preferred in providing an intended clinical benefit. In some situations, a zero order release profile is preferred while in others a first order release profile or a sigmoid release profile is observed.
Osmotic devices manufacture with two or more layers in order to provide a desired release rate profile can be difficult to produce and require specialized manufacturing machinery. Therefore, it would be an improvement in the art to provide a controlled release dosage form that is easily manufactured and produces a desired release rate or release rate profile for a desired soluble or insoluble hydrochloride salt of an active agent by modifying the amount of sodium chloride in the core of the osmotic device.